Molecule for functionalizing a support, attachment of a radionuclide to the support and radionuclide generator for preparing the radionuclide, and preparation process

ABSTRACT

Molecule for attaching a radioactive parent nuclide to a support, comprising at least one functional group for attaching the radioactive parent nuclide; and a molecular moiety suitable for establishing a nonpolar bond to the support.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/700,478, filed Feb. 4, 2010, which claims priority under 35 U.S.C.§119 of German Patent Application No. 10 2009 007 799.5, filed Feb. 6,2009, which is incorporated herewith by reference in its entirety.

BACKGROUND OF THE INVENTION

The invention relates to a molecule for functionalizing the surface ofan inert support and to the use in the preparation of a radionuclide ofhigh purity in a generator. The invention relates in particular to amolecule for attaching a radioactive parent nuclide, in particulargermanium-68, to a support.

Radionuclides, in particular positron emitters, are used in positronemission tomography (PET). In the PET examination of a patient, thedistribution of a weakly radioactive, positron emitter-labelledsubstance such as, for example, a biomolecule is visualized in anorganism via the radioactive disintegration of the positron emitter,using a detector.

Since biomolecules participate in the normal metabolism of the organism,accumulating in the process inter alia in tumour cells, PET can beutilized for identifying tumour cells.

One example of a radionuclide preferred for PET is gallium-68, which canbe obtained using a germanium-68/gallium-68 radionuclide generatorsystem (1, 2). With a half-life of 67.63 minutes, the isotope gallium-68disintegrates with emission of a positron. By virtue of its physical andchemical properties, gallium-68 is highly suitable for nuclear medicalexaminations. Owing to its short half-life, it is particularly suitablefor radiolabelling biomolecules.

Gallium-68 can be generated by radioactive disintegration from theparent nuclide germanium-68 which disintegrates with a half-life of270.8 days.

In the generator, the germanium-68 is attached to an insoluble matrix ofan inert support, where, by continuous disintegration of the germanium,gallium-68 is constantly formed and may be extracted from the generatorby elution with a solvent.

The radionuclides used for labelling the radio-pharmaceutics have tomeet high quality standards. In particular, the radionuclides generatedhave to have a high degree of purity and must be free from metallicimpurities since these may, owing to competing reactions, have anadverse effect on the labelling of the radiopharmaceutics, and mayreduce the technically achievable yield (3-5).

As support for the stationary phase, known germanium-68/gallium-68generator systems use inorganic ion exchange substances, such as, forexample, TiO₂, SnO₂, Al(OH)₃. However, in a disadvantageous manner, thegallium-68 extracted therewith contains metallic impurities, such thatthe original eluate has to be purified prior to use in aradiopharmaceutic (4, 5).

As an alternative to inorganic ion exchange substances, generators use,as supports, organic polymers to which, with the aid of functionalgroups, individual molecules having a high affinity for germanium areattached. Such molecules may, for example, be pyrogallol or catecholwhich, via phenolic hydroxyl groups, form stable complexes withgermanium (FIG. 1A) (6).

In a known germanium-68/gallium-68 generator, the support used is aresin prepared from pyrogallol and formaldehyde (4-7). During thepreparation of the germanium-specific resin, pyrogallol is immobilizedon the support by copolymerization with formaldehyde. However, theapplicability of these materials and generator systems is limited.

Thus, with the germanium-68/gallium-68 generators mentioned above basedon organic polymer, gallium-68 can be obtained only in concentrated acidsolutions (3-6M). This requires reprocessing of the eluate prior to useas radiopharmaceutic.

In addition, the process for synthesizing the pyrogallol/formaldehyderesin is technically very demanding and expensive. In addition, the maincomponent of the formaldehyde matrix is toxic, such that the preparationof an injectable radiopharmaceutic requires additional purificationsteps.

OBJECTS OF THE INVENTION

It was an object of the present invention to provide a substance forpreparing a radionuclide using a generator, where a radionuclide can beattached to a support which can be used as stationary phase in thegenerator, and which allows the radionuclide to be prepared with a highdegree of purity and without impurities, and also a correspondinggenerator and a preparation process.

The object is achieved by a molecule having the features according toclaim 1.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, a molecule for attaching a radioactiveparent nuclide to a support is provided which comprises at least onefunctional group for attaching the radioactive parent nuclide and amolecular moiety suitable for establishing nonpolar bonds to thesupport.

By virtue of the nonpolar bond to the support, in an aqueous solutionwhich can be used for eluting the daughter nuclide in a generator, theradioactive parent nuclide cannot be detached from the support material.It is thus possible to avoid contamination of the eluate, and to extendthe lifespan of the generator for subsequent elutions.

The radioactive parent nuclide may comprise germanium—whichdisintegrates to gallium-68. It is thus possible to provide a supportfor a germanium-68/gallium-68 generator which allows the preparation ofhighly pure gallium-68 substantially without impurities, in particularmetallic impurities, and with a high degree of purity and preferablywithout further preparation steps prior to use in a radiopharmaceutic.The degree of purity that can be achieved is preferably less than 1 ppm,with preference less than 100 ppb, particularly preferably less than 10ppb or even less than 1 ppb of impurities.

According to one embodiment, the functional group for attaching theparent nuclide comprises a hydroxyl group and preferably a phenolichydroxyl group. The molecule may also comprise a plurality of functionalgroups such as, for example, two, three or more functional groups. Withthe aid of the functional group, which has a high affinity to germanium,thus allowing quantitative adsorption of the germanium from the liquidphase, it is possible to form stable complexes with germanium molecules.

According to a preferred embodiment, the parent nuclide is germanium-68and the functional group is pyrogallol or catechol.

According to a further preferred embodiment, the molecular moietysuitable for establishing a nonpolar bond to the support is hydrophobic.Using a hydrophobic molecular moiety, the molecule can be attached via anonpolar bond to an inert support or be immobilized thereon, preventinginter alia a dissolution of the molecule and the parent nuclide attachedthereto in an aqueous solution.

In contrast, known compounds having one or more germanium-specificfunctional groups such as, for example, catechol and pyrogallol, arehighly soluble in aqueous solutions. It is not possible to attachcatechol and pyrogallol directly to an inert support such that the bondwithstands extraction of the daughter nuclide from the generator usingan aqueous solution. The solubility in water of catechol and pyrogallolis 450 g/1 and 400 g/l, respectively.

Using derivatives of molecules which, in addition to at least onegermanium-specific functional group, additionally have a hydrophobicmolecular moiety, it is possible to achieve insolubility in water.

According to a further preferred embodiment, the hydro-phobic molecularmoiety is selected from the group consisting of:

-   (i) aromatic and heteroaromatic moieties, such as, for example,    benzene, naphthalene, quinoline;-   (ii) saturated or unsaturated fatty acids having more than 3 carbon    atoms, preferably from 3 to 20 carbon atoms;-   (iii) branched or straight-chain alkyl chains having more than 3    carbon atoms, such as, for example, octyl, decyl, or octadecyl    groups, preferably having from 3 to 20 carbon atoms.

According to a preferred embodiment, the molecule is an organic moleculeselected from the group consisting of 2,3-dihydroxynaphthalene anddodecyl 3,4,5-trihydroxy-benzoate.

According to a further preferred embodiment, the support is selectedfrom the group consisting of an organic support and an inorganicsupport, such as, for example, silica gel.

The invention furthermore provides a support for use as stationaryphase, comprising at least one molecule according to the inventionaccording to any of the embodiments described above and which isattached to the support via a nonpolar bond.

The invention furthermore provides a generator for a radioactivedaughter nuclide, in particular gallium-68, comprising a moleculeaccording to the invention according to any of the embodiments describedabove, a support, the molecule being attached to the support via anonpolar bond, and a parent nuclide, in particular germanium-68, whichis attached to the molecule via the functional group.

The invention furthermore provides a process for preparing a radioactivedaughter nuclide which comprises the following steps: providing agenerator comprising a support and a parent nuclide to which a moleculeaccording to the invention according to any of the embodiments describedabove is attached, where the molecule is attached to the support via anonpolar bond, and eluting the daughter nuclide.

Using the generator according to the invention, it is possible toprepare gallium-68 with a particularly high degree of purity, metallicimpurities and other residues from the generator being substantiallyavoidable. The generator can be prepared with low expense and in acost-effective manner.

According to a further preferred embodiment, the process comprisescharging the generator with silica gel as support, to which silica gelthe molecule is applied.

According to yet another embodiment, the process comprises bringing thesupport into contact with the parent nuclide in a solution. Suitablesolvents are the following substances: water, aqueous acids, solutions,salt solutions, such as, for example, buffer solutions, organicsolutions based on alcohol, ether, etc.

According to a further preferred embodiment, the parent nuclide maycomprise germanium-68 which disintegrates to gallium-68.

Finally, the invention comprises the use of a molecule according to anyof the embodiments indicated above for preparing pure gallium-68.

FIGS. 1a, b show the structural formulae of catechol (FIG. 1a ) andpyrogallol as compounds having germanium-specific functional groups;

FIGS. 2a, b show the structural formulae of examples of moleculesaccording to the invention such as 2,3-dihydroxynaphthalene (FIG. 2a )and dodecyl 3,4,5-trihydroxybenzoate.

EXAMPLE

A germanium-specific resin was prepared by coating inert silica gel withdodecyl 3,4,5-trihydroxybenzoate having the structural formula shown inFIG. 1b . The resin was used for preparing small chromatographiccolumns. An aqueous solution comprising the radio-nuclide germanium-68having an activity in the range between 20 and 1250 MBq was then pumpedthrough the columns. During this step, the germanium-68 was adsorbedquantitatively on the columns.

The columns charged with germanium-68 were then used to prepare theshort-lived gallium-68. It was possible to repeatedly eluate thegallium-68 generated by the germanium-68 absorbed on the support. Theelution of gallium-68 was effected using weak hydrochloric acidsolutions (0.05 M HCl) having a low volume of up to 2.5 ml. Leakage ofthe parent nuclide germanium-68 was in the range 1×10⁻⁴−3×10⁻³%. Thegallium-68 could be used directly and without further chemicalreprocessing for preparing injectable gallium-68 radio-pharmaceutics.

LITERATURE REFERENCES

-   1) Al-Nahhas A, Win Z, Szysko T, Singha A, Nannil C, Fanti S,    Rubello D. Gallium-68 PET: A New Frontier in Receptor Cancer    Imaging. Anticancer research. 2007; 27: 4087-4094-   2) Helmut M, Hofmann M, Haberkorn U. ⁶⁸Ga-Labeled Peptides in Tumor    Imaging. J Nuc Med. 2005; 46: 172S-178S-   3) Breeman W, Jong M, Blois E, Bernard B, Konijnenberg M,    Krenning E. Radiolabelling DOTA-peptides with ⁶⁸Ga. Eur J Nuc Med    Mol Imaging. 2005; 32: 478-458-   4) Meyer G-J, Mäcke H, Schuhmacher J, Knapp W, Hofmann M.    ⁶⁸Ga-labelled DOTA-derivatised peptide ligands. Eur J Nuc Med Mol    Imaging. 2004; 31: 1097-1104-   5) Zhernosekov K, Filosofov D, Baum R, Aschoff P, Bihl H, Razbash A,    Jahn M, Jennewein M, Rösch F. Processing of generator-produced ⁶⁸Ga    for medical application. J Nuc Med. 2007; 48: 1741-1748-   6) Patent DE 29 32 948 A1-   7) Schuhmacher J, Maier-Borst W. A new ⁶⁸Ge/⁶⁸Ga radio-isotope    generator system for production of ⁶⁸Ga in dilute HCl. I J Appl Rad    Isotopes. 1981; 32: 31-36

The invention claimed is:
 1. An organic or inorganic support for use asstationary phase, the support comprising: resin or silica gel, and acompound comprising: pyrogallol or catechol, and a saturated orunsaturated fatty acid having more than 3 carbon atoms, or a branched orstraight-chain alkyl chain having more than 3 carbon atoms.
 2. Thesupport of claim 1, where the branched or straight-chain alkyl chainhaving more than 3 carbon atoms is one of an octyl, decyl or octadecylgroup.
 3. The support of claim 1, where the compound is dodecyl3,4,5-trihydroxybenzoate or 2,3-dihydroxynaphthalene.
 4. The support ofclaim 1, where the support is coated with the compound.